Oxygen, a critical element in many biological systems, was independently discovered by Priestly and Sheele in 1774. Shortly thereafter, Lavoisier reported on the poisonous effects of oxygen inhalation and in 1878, Bert documented the poisonous effects of high oxygen tension levels on non-human animals (See, Knight, Ann. Clin. Lab. Sci., 28:331–346 [1998]). Experiments conducted as early as 1899 demonstrated that increased oxygen tension results in severe pulmonary congestion with pneumonia-like changes in mice, rats, and guinea pigs (See, Knight, supra). Indeed, in a 1909 medical text, it is indicated that “ . . . there can be little doubt that the administration of oxygen may not be entirely harmless as stated in previous editions . . . ” (as quoted by Knight, supra, at page 332). Thus, oxygen toxicity has long been recognized as a problem in physiological systems. However, the information regarding oxygen toxicity remained largely ignored by physicians for several decades. Significantly, the failure to recognize the potential toxic effects of increased oxygen tension resulted in an estimated 10,000 cases (worldwide) of blindness in newborns due to retrolental fibroplasia between the 1940s and 1950s (See, Knight, supra).
Final acceptance of the medical community that increased oxygen tension is potentially toxic to humans and other animals did not occur until a publication in 1967, which correlated the concentration and duration of inspired oxygen before death with pathologic lung findings at autopsy. The following year, the formation of pulmonary hyaline membranes in adults was associated with oxygen toxicity. In 1954, the hypothesis was presented that oxygen poisoning and X-irradiation have a common basis of action through the formation of oxidizing free radicals (See, Knight, supra). Nonetheless, it was not until the discovery of superoxide dismutase in 1969, that the presence of free radicals in biological systems was generally considered to be likely.
Today, the potential for damage caused by oxygen and oxygen radicals is well-recognized. Indeed, oxygen has been referred to as a “double-edged sword,” (See, Knight, supra). Of course, oxygen is critical for most life forms, including humans. However, in order to benefit from the advantages provided by aerobic respiration, organisms have developed antioxidant enzymes and other means to detoxify reaction oxygen species and maintain essentially anaerobic conditions throughout all tissues, organs, and/or the vascular system. Without antioxidant enzymes (e.g., superoxide dismutases such as MnSOD and CuZnSOD), there is the possibility of damage to many biological molecules (e.g., DNA, RNA, proteins, and lipids). Accumulation of oxidatively damaged molecules leads to genetic mutations and cellular senescence. Indeed, any factors that compromise the activities of antioxidants may result in the accumulation of reactive oxygen species and the resultant damage caused by their action. It has also been suggested that decreasing antioxidant activities is associated with the aging process (See, Tian et al., Free Radical Biol. Med., 24:1477–1484 [1998]).
Oxygen therapy has been used for decades in various clinical settings. However, many essential intracellular reactions involving oxygen result in the formation of free radicals, and prolonged oxygen therapy is associated with a significant risk of toxicity. For example, exposure to pure oxygen leads to diffuse alveolar damage, with plasma exudation into the alveolar space. The subsequent death of endothelial and alveolar epithelial cells appear to be essential features of oxygen-induced alveolar damage, with the damaged cells exhibiting the effects of apoptosis (condensation and margination of chromatin) and necrosis (disruption of the plasma membrane) (Barazzone et al., Am. J. Resp. Cell Mol. Biol., 19:573–581 [1998]). Indeed, present recommendations indicate that humans should not be exposed to oxygen concentrations greater than 60% for prolonged time periods (See, Knight, supra).
In the surgical setting, oxygen toxicity is often observed in situations involving lung injury (e.g., postpneumonectomy pulmonary oedema [PPO]). PPO may be indistinguishable from severe acute respiratory distress syndrome (ARDS) or the less serious syndrome, acute lung injury (ALI). PPO is a significant operative concern, with reports indicating that PPO is a complication in 4–7% of pneumonectomies and 1–7% of lobectomies, and has an associated mortality rate of 50–100% (See, Williams et al., Eur. Respir. J., 11:1028–1034 [1998]). Ischemia-reperfusion injury has also been considered a contributor to PPO, related to lung damage caused by operative ischemia and injury caused by formation of reactive oxygen species during reperfusion. Despite improvements in therapies and management, the mortality rate in acute lung injury remains high. While these cases have involved injuries to lung tissues resulting from exposure to increased oxygen tensions, other organs and tissues have proven to be equally at risk from this type of exposure. In addition, problems associated with the formation of adhesions may be related to oxygen exposure of the tissues during surgery.
Oxidative myocardial injury due to oxygen-derived free radicals and nitric oxide has been shown to occur during hyperoxic (i.e., 300 to 400 mm Hg) cardiopulmonary bypass surgery. This has led to recommendations that reduced oxygen tension levels be utilized during cardiac operations (i.e., “normoxic” levels of about 140 mm Hg) (See, Ihnken et al., J. Thorac. Cardiovasc. Surg., 116:327–334 [1998]). This has been shown to be of particular importance in hypoxemic immature hearts (See, Morita et al., J. Thorac. Cardiovasc. Surg., 110:1235–1244 [1995]). Furthermore, reoxygenation of organs such as hearts may also cause injury (e.g., lipid peroxidation and functional depression) that may result in perioperative cardiac dysfunction (Ihnken et al., J. Thorac. Cardiovasc. Surg., 110:1171–1181 [1995]). In addition, cardiopulmonary bypass patients undergoing heart valve replacement surgery appear to be under oxidative stress, as compared with normal controls.
There are two additional episodes of oxidative stress that occur during bypass surgery (See, Pepper et al., Free Rad. Res., 21:377–385 [1994]). The first is produced when the patient is placed on extracorporeal blood circulation and oxygenation, which results in lipid peroxide and thiobarbituric acid-reactive substance increases. The second episode occurs during reperfusion of the myocardium following removal of the aortic cross clamp. This removal ends a period of ischemia and subjects the myocardium to reperfusion or reoxygenation injury. This injury is amplified by pro-oxidant biochemical changes resulting from extracorporeal oxygenation and blood circulation, as well as the effects of hemodilution.
In the central nervous system, oxidative injury can result in tremendous damage. For example, oxidative stress has been associated with such severe syndromes as Parkinson's disease and Alzheimer's disease and familial amyotrophic lateral sclerosis (ALS) (See, Satoh et al, Cell. Mol. Neurobiol., 18:649–666 [1998]).
The situation is similar in the transplantation setting. For example, during long-term in vitro preservation and reperfusion of hearts for transplantation, irreversible tissue damage occurs due to reactive oxygen species. Thus, efforts have been made to inhibit the generation of oxygen-derived free radicals and the associated oxidative damage of ischemic tissue through the use of cold conditions and specially formulated buffer solutions (See, Sellke et al., J. Surg. Res., 80:171–176 [1998]; Cargnoni et al., J. Heart Lung Transplant., 18:478–487 [1999]). Nonetheless, the time limits for donor organ transport remain limited to several hours.
Thus, it is clear that what is needed are improved methods and devices that reduce the potential for oxidative injury during surgical procedures, as well in the transport of samples, organs/tissues, etc. It is also clear that improved methods are needed which allow the operator (i.e., surgeon) to carefully control and monitor the gases in the theater surrounding a surgical field as appropriate for the surgical procedure.